This invention relates to an improvement in the production of benzylated amines by the reaction of an amine with a benzyl halide. In particular this invention provides a high-yield process wherein a key by-product of the reaction, hydrogen halide, is removed from the system in an efficient manner.
The production of benzphetamine by the reaction of methamphetamine with benzyl chloride produces large amounts of hydrogen chloride (HCl) by-product that must be neutralized and removed from the system. This is currently carried out by the addition to the reaction mixture of a large amount of a base, sodium carbonate, to neutralize said by-product. While this means achieves the removal of the by-product hydrogen chloride, sodium carbonate is added in the solid state thereby requiring energy to thoroughly mix the solid carbonate in the liquid reaction product to achieve complete reaction. Furthermore, the neutralization reaction forms carbon dioxide gas and water that tends to provide foaming and caking problems and greatly slows the neutralization reaction. Consequently, it is likely that some of the hydrogen chloride is scavenged by methamphetamine forming methamphetamine hydrochloride. Higher reaction temperatures and longer reaction times are then needed to force the solid sodium carbonate to neutralize the solid methamphetamine hydrochloride and regenerate the reactive methamphetamine base. The tendency of solid sodium carbonate to form deposits on the walls and other internal surfaces of the reactor further reduces the effectiveness of such base added to the liquid reaction product.
In an attempt to improve the efficiency of the neutralization of by-product hydrogen chloride in the process for producing benzphetamine, other bases have been considered but all have demonstrated disadvantages that are prohibitive to their use. For example, triethylamine in the reaction mixture for the purpose of neutralizing by-product hydrogen chloride was determined to be unsatisfactory. Triethylamine has a boiling point of 85° C. that may suppress the 120° C. temperature range of the reaction mixture thereby causing significant refluxing. Also, such an amine may react with benzyl chloride forming benzyltriethylammonium salt. An amine that competes with the methamphetamine for the benzyl chloride is undesirable and the resulting quaternary ammonium salt may interfere with the isolation and purification of the product.
The literature contains reference only to sodium carbonate as a neutralizing agent for by-product hydrogen chloride in a reaction between methamphetamine and benzyl chloride to produce benzphetamine. Attempts to reduce the problems involved with acid by-product removal, has included reducing the addition of sodium carbonate and adding a diluent such as toluene to the reaction mixture. Also, slowing the rate of addition of benzyl chloride improved foaming condition but all such approaches were not considered sufficient improvements compared with the disadvantages involved with such modifications.
While the use of amines as described above have not shown sufficient advantage in the present reaction of interest, other reactions involving related compounds have employed amines to neutralize acid by-product. In U.S. Pat. No. 6,399,828, to Boswell et al. ammonium formate was employed in the catalytic hydrogenation reaction of O-acetylnorephederine. In U.S. Pat. No. 5,536,877 there is disclosed a process for preparing aryl benzylamine by the reaction of aryl amines with a benzyl chloride in the presence of both a phase-transfer catalyst and an inorganic base. Excess base selected from inorganic bases and weak organic acids are employed. In U.S. Pat. No. 1,854,553 there is disclosed a process for preparing ethyl benzylaniline by the reaction of monethyl aniline and benzyl chloride in toluene. Soda ash is employed in the purification of the product.
To indicate the lack of predictability of attempts to neutralize acid by-product by means of amine-addition there is disclosed in U.S. Pat. No. 5,449,828 prior art problems with the preparation of propargyl ammonium chloride. It is disclosed therein that excess amine to bind excess hydrogen bromide in such process could not be employed because the problem of recovering the amine could not be solved. The neutralizing scheme disclosed in this patent employed an aqueous tartaric acid buffer system comprising ammonium hydroxide and basic alkali salts.
In U.S. Pat. No. 5,220,068, there are disclosed reactions to provide psycho stimulant agents by the reaction of various benzyl derivatives containing a halogen with alkyl amines or a halogenated amine with a benzyl amine. It is disclosed that various acid-binding agents may be employed including excess amine starting material, organic or inorganic bases or basic ion-exchange resins.
Other references disclosing the use of excess amine reactant include U.S. Pat. No. 5,198,587, a process for preparing phenethylamine and U.S. Pat. No. 2,987,548, a process for preparing benzylamine. In U.S. Pat. No. 2,490,813 there is disclosed a reaction of chlorobenzene with an organic amine in the presence of a copper chloride catalyst. An excess of amine was employed for the purpose of neutralizing the hydrogen chloride by-product. Also, a recycle scheme is disclosed wherein the excess amine was recovered and recycled to the reactor after basification to remove the hydrogen chloride from the amine. However, the process could not prepare a benzylamine because it employs a phenyl halide.